Impact of underlying diabetes and presence of lung cavities on treatment outcomes in patients with pulmonary tuberculosis.

AIMS: We investigated the effects of diabetes and the presence of lung cavities on treatment outcomes in patients with pulmonary tuberculosis. METHODS: We conducted a retrospective review of the clinical records of all consecutive patients admitted to the Kanagawa Cardiovascular and Respiratory Centre with the diagnosis of pulmonary tuberculosis. The study outcomes examined were time to sputum culture conversion and percentage of patients with sputum culture conversion by the time 2 months of treatment, and these outcomes were compared between patients with and without diabetes. RESULTS: Of the 260 patients enrolled in the study, 69 were diagnosed as having diabetes mellitus, while the remaining 191 did not have diabetes. The percentage of patients with cavities was higher in the patients with diabetes (71.0%) than in those without (45.5%; P = 0.0003). The time to sputum culture conversion was significantly longer in the patients with diabetes than in those without (P = 0.0005), and the percentage of patients with a positive sputum culture at 2 months was higher in the patients with diabetes (43.5%) than in those without (18.8%; P = 0.0001). Multivariate analyses revealed that the presence/absence of lung cavities was a more important determinant of treatment outcomes than the presence/absence of diabetes. CONCLUSIONS: The presence of lung cavities was found to be a more important determinant of the treatment outcomes than that of diabetes per se in patients with pulmonary tuberculosis.

Effect of HIV infection on the frequency of cytokine-secreting cells in human peripheral blood.

A selective decrease in type 1 cytokine secretion by in vitro stimulated peripheral blood cells is reportedly associated with disease progression in HIV-infected individuals. To examine whether a similar change in cytokine secretion occurs under physiologic conditions in vivo, sensitive and specific ELIspot assays were used to compare the phenotype and frequency of PBMC spontaneously producing interleukin (IL)-2, IL-4, IL-10, and interferon-gamma (IFN-gamma) in 83 HIV-infected subjects and 60 normal controls. Phenotypic analysis of freshly isolated cytokine-secreting cells showed that T cells were the primary source of IL-2, IL-4, and IFN-gamma while CD14+ macrophages/monocytes were the dominant source of IL-10 in vivo. The number of peripheral blood mononuclear cells (PBMC) spontaneously secreting both type 1 and type 2 cytokines was significantly reduced in HIV-infected patients versus controls. The magnitude of this decrease did not correlate with disease severity. Changes in IL-2-secreting cell number correlated with CD4 count, while changes in the frequency of IFN-gamma-secreting cells correlated with disease duration. These findings do not support the contention that a selective reduction in type 1 cytokine production correlates with disease progression.

Preferential proliferation of anti-DNA producing cells of NZB mice in NZB.xid recipients.

B cells from autoimmune NZB mice were transferred into unmanipulated non-autoimmune NZB.xid mice. The number of antibody-producing cells against various antigens in recipient mice was monitored at varying time after cell transfer using ELISPOT assay. NZB B cells producing antibody against all antigens we examined were able to proliferate in NZB.xid mice, which supports the idea of polyclonal B cell activation. However, anti-DNA producing cells proliferated most rapidly, and anti-BrMRBC producing cells proliferated more rapidly than B cells of other antigenic specificities. The percentage of anti-DNA producing cells in total immunoglobulin-producing cells increased over time whereas the percentage of anti-ovalbumin producing cells kept the same level. This indicates directly the preferential proliferation of NZB anti-DNA producing cells in NZB.xid mice. The result shows the responsibility of antigen-specific stimulation or activation on autoimmunity in the context of polyclonal B cell activation.

Quantitation of autoantibody-secreting B cells in systemic lupus erythematosus.

An ELISA spot assay was used to quantitate the number of autoantibody-secreting B cells in the peripheral blood of patients with systemic lupus erythematosus. Patients with active disease had 20 fold more anti-DNA, 4 fold more anti-actin and 3 fold more anti-myosin secreting lymphocytes than controls but normal numbers of anti-cardiolipin and anti-transferrin secreting B cells. 60% of SLE patients had increased numbers of B cells reactive with multiple autoantigens. These data suggest that B cell activation in SLE may be influenced by both antigen-specific and antigen-independent factors.

Abnormal numbers of cytokine producing cells in patients with polymyositis and dermatomyositis.

OBJECTIVE: To examine the constitutive pattern of cytokine production in patients with polymyositis (PM) and dermatomyositis (DM). METHODS: PBMC secreting the type 1 cytokines IL-2 and IFN gamma and the type 2 cytokines IL-6 and IL-10 were monitored by ELIspot assay. RESULTS: The frequency of IFN gamma-secreting PBMC was reduced 2-20 fold in patients with PM and DM when compared to normal controls (p < 0.01). This change correlated inversely with disease activity (p < 0.01). PM and DM were also characterized by increased numbers of cells secreting IL-10. Patients with DM had fewer IL-2 (p < 0.03) and more IL-6 (p < 0.006) secreting cells than normal controls or patients with other myopathies. CONCLUSIONS: Abnormal patterns of cytokine production characterize patients with PM and DM.

[Two cases of HIV infection accompanied with borderline personality disorder].

We report here two cases of HIV infection with a borderline personality disorder. Case 1 was a 25-year-old male patient who was diagnosed with HIV infection 4 years ago. Borderline personality disorder was also diagnosed at that time. Although he was referred to our hospital in 1999, we had to refer him to another hospital for his regular outpatient hemodialysis. Case 2 was a 24-year-old male patient who had borderline personality disorder since 1996. He was diagnosed with HIV infection in 1999 and referred to our hospital. He ignored rules in visiting clinics such as prior reservations and frequently called doctors, case-workers and nurses. After several visit he intentionally took excessive sedative medicines and called a case-workers at our hospital. He was admitted to our hospital for three days. After he was discharged, we set limitations for his behavior not to harm himself and to obey the rules in visiting clinics. In other countries investigators report that borderline personality disorder is more common in HIV-infected persons. It may be because persons with borderline personality disorder are more likely to engage in high-risk sexual behavior, which is also applicable to these two cases. As HIV infection is rapidly prevailing in Japan, it is possible that the chance are that this disorder will be seen more frequently in HIV infected cases.

[Successful treatment of primary CNS lymphoma diagnosed by 201thallium-single photon emission computed tomography (201Tl-SPECT) with whole-brain radiation therapy in an AIDS patient].

The patient, a 51-year-old male with a two year history of AIDS, was admitted to our hospital because of hemiparalysis and vomiting. The MRI study showed multiple lesions with ring-enhancement in the right basal brain area. Empirical therapy for toxoplasma encephalitis was started. After 64 days, the subsequent brain MRI showed deterioration. A 201Tl-SPECT study was performed and the findings were consistent with those of malignant lymphoma (ML). The patient was treated with 40 Gy of whole brain radiation, MRI showed partial response to this therapy, and clinical improvement was achieved. The definitive diagnosis of primary CNS lymphoma can be made only by brain biopsy, and many cases have been diagnosed at autopsy. The clinical and radiological findings of primary CNS lymphoma resemble toxoplasma encephalitis. An empirical therapy for toxoplasma encephalitis is recommended to avoid brain biopsy in these cases. The use of 201Tl-SPECT for the differential diagnosis of these diseases have been reported. Considering the poor prognosis of primary CNS lymphoma in AIDS, the application of 201Tl-SPECT before empirical therapy for toxoplasma must be important for appropriate treatment.

[Successful therapy with cyclosporine in a case with interstitial pneumonitis associated with polymyositis].

We describe a case of interstitial pneumonitis associated with polymyositis who responded well to cyclosporine therapy. In October, 1993, a 49-year-old female was admitted to our hospital because of fever, muscle weakness and progressive dyspnea. Interstitial pneumonitis with polymyositis was diagnosed and daily oral steroid therapy was started. As the therapy was ineffective, pulse intravenous steroid therapies followed by oral cyclophosphamide and steroid therapy was given. Whereas serum levels of muscle enzymes decreased, she became progressively hypoxemic. No effect was observed in series of therapy including additional pulse steroid therapy, pulse intravenous cyclophosphamide therapy, oral azathioprine and oral bethametazone therapy. In April, 1994, oral cyclosporine was started. After daily oral cyclosporine was combined with steroid, her symptoms, chest X-ray, chest CT and pulmonary function tests significantly improved. Her disease became stable and there was no signs of recurrence since then. It is suggested that cyclosporine is useful for the treatment of progressive interstitial pneumonitis associated with polymyositis.

[Cytomegalovirus antigenemia assay as a useful tool for early diagnosis and therapy for cytomegalovirus infections in three cases with collagen diseases].

We report here three cases of collagen diseases with cytomegalovirus infections. (1) A 21-year-old female, who had been diagnosed as systemic lupus erythematosus, lupus nephritis and lupus peritonitis, had fever. Cytomegalovirus antigenemia (CMV-Ag) assay was 10/8 positive. (2) A 33-year-old female, who had been diagnosed as Wegener glanulomatosis, had fever and liver dysfunction. CMV-Ag assay was 933/896 positive. (3) A 64-year-old female, who had been diagnosed as microscopic polyangitis, had fever, liver dysfunction and pneumonia. CMV-Ag assay was 6/2 positive. They were considered to be complicated with CMV infections. We could make early diagnoses of CMV infection by using CMV-Ag assay and treat them with anti-CMV therapy effectively.

[Pulmonary hypertension in a patient with primary Sjogren's syndrome, Hashimoto's disease, and primary biliary cirrhosis].

A 53-year-old woman was admitted to our hospital in May 1999, because of progressive dyspnea and liver dysfunction. She had been receiving the replacement therapy of thyroid hormone for thirteen years and suffering from Raynaud's phenomenon for 9 years. She experienced exertional dyspnea and sicca symptom for 3 years, and had an episode of syncope 4 months before admission. An echocardiogram showed dilation of the right ventricle, tricuspid regurgitation and the estimated mean pressure of the pulmonary artery was higher than 120 mmHg. She was diagnosed as having severe pulmonary hypertension (PH) complicated with primary Sjogren's syndrome and primary biliary cirrhosis without portal hypertension She was treated with anticoagulant (warfarin) and oral prostagrandin I2 (prostacyclin). However, right heart failure and jaundice gradually progressed and she suddenly died in December 1999. At autopsy, the heart was enlarged with right ventricular hypertrophy. Small arteries and arterioles in the lung showed concentric intimal proliferation and severe plexogenic vascular disease. Deposition of immunoglobulin was not observed in the pulmonary arteries. Since the prognosis of PH is poor, it is important to analyze the etiology of the disease for the development of the treatment.

[Hematological abnormalities of primary Sjogren's syndrome].

Sjogren's syndrome (SS) is an autoimmune disease characterized by a chronic inflammatory response mainly localized to the lacrimal and salivary glands. However, it sometimes involves extraglandular organs culminating in systemic disorders. Hematological abnormalities are not uncommon, although they rarely have clinical significance. In this study we examined 99 patients with primary SS who visited our hospital during 1989 to 1999. Patient's mean age was 54.1 years and 95 out of 99 were female. Lymphopenia and leukopenia was noted in 35 patients (35.3%) and 26 patients (26.2%) respectively, and 7 patients (7.1%) had thrombocytopenia. 43 patients (43.4%) had either of these hematological abnormalities. Patients with lymphopenia showed significantly low frequency of arthralgia and anti-SS-A/B antibody was more common in this group. Only one patient in this group required prednisolone therapy because of polyarthritis and general fatigue while others needed no specific therapy. Patients with thrombocytopenia were significantly younger and a male/female ratio was higher than those without this abnormality. They had higher tendency to accompany with skin eruption, positive anti-SS-B antibody, anti-nuclear antibody and rheumatoid factor. Three out of 8 patients with thrombocytopenia were treated with prednisolone according to the protocol for idiopathic thrombocytopenic purpura. All of 3 patients had positive PA-IgG and normocellular bone marrow. Autoimmune mechanism such as polyclonal B cell activation may play a role in the pathogenesis of thrombocytopenia.

Altered frequency of type 1 cytokine secreting cells in the peripheral blood of patients with primary Sjögren's syndrome.

OBJECTIVE: An imbalance in immunoregulatory cytokines may contribute to the etiopathogenesis of Sjogren's syndrome (SS). We investigated systemic abnormalities in cytokine production in the peripheral blood in patients with SS. METHODS: ELISPOT assays were used to detect and enumerate cells spontaneously secreting interleukin 2 (IL-2), IL-6, IL-10, and interferon-gamma (IFN-gamma) in freshly isolated peripheral blood mononuclear cells from 20 patients with SS and 20 healthy controls. RESULTS: The number of cells spontaneously secreting type 1 cytokines IL-2 and IFN-gamma was decreased in the peripheral blood of patients with SS compared to controls. There was no change observed in the number of cells spontaneously secreting IL-6 and IL-10. Cells spontaneously secreting IL-4 were too rare in peripheral blood to evaluate, although cells capable of secreting IL-4 in response to phytohemagglutinin did not differ from controls. Patients with severe extraglandular symptoms (such as vasculitis) had a significantly lower frequency of IFN-gamma secreting cells in their peripheral blood than those without extraglandular involvement. CONCLUSION: These results suggest that decreased type 1 cytokine production may contribute to or reflect the pathogenesis of SS.

Phenotype and frequency of cells secreting IL-2, IL-4, IL-6, IL-10, IFN and TNF-alpha in human peripheral blood.

The phenotype and frequency of cells in normal human peripheral blood spontaneously secreting IL-2, IL-4, IL-6, IL-10, IFN and TNF-alpha ex vivo was determined using ELIspot assays. CD4+ T cells were the dominant source of IL-2 and IL-4 while multiple cell types (primarily CD8+ lymphocytes) produced IFN. Fewer than 0.05% of mononuclear cells were spontaneously secreting these T cell derived factors. By comparison, IL-6, IL-10 and TNF-alpha were produced by 0.7-20% of PBMC. The primary sources of the latter cytokines were CD14+ macrophages/monocytes. A significant positive correlation was found in the frequency of cells secreting IL-6, IL-10 and TNF-alpha ex vivo, suggesting that the release of such factors was coordinately regulated. No such correlation was found among IL-2, IL-4 and IFN secreting cells, indicating that the production of predominantly T cell derived cytokines was regulated independently.

IL-12 enhances lymphoaccumulation by suppressing cell death of T cells in MRL- lpr/lpr mice.

Lymphoaccumulation occurs in MRL- lpr/lpr mice, because double-negative T cells (DNT cells) cannot be deleted due to their Fas mutation, i.e., lpr. We show here that IL-12 enhances in lymphoaccumulation by suppressing cell death of DNT cells in [corrected] MRL- lpr/lpr mice. It has been reported that viable DNT cells from MRL- lpr/lpr mice undergo rapid apoptosis in ordinary cell culture without additional stimulation, suggesting that unknown in vivo factors other than lpr suppress the apoptosis. In the present study, we found that plasma IL-12p40 monomer and/or homodimer level increased with age in MRL- lpr/lpr but not in MRL-+/+ mice, and the increase in IL-12 correlated well with lymphoaccumulation. Requirement of IL-12 in lymphoaccumulation and in suppressed cell death of DNT cells of MRL- lpr/lpr mice was assessed. When an antibody neutralizing IL-12 was injected into old MRL- lpr/lpr mice with high plasma IL-12 level, lymphoaccumulation was diminished. When IL-12p40- or IL-12p70-encoding plasmid was administered to young MRL- lpr/lpr mice before the plasma IL-12 level increases, lymphoaccumulation was enhanced. The ordinary cell culture-induced cell death of DNT cells from MRL- lpr/lpr mice was suppressed in the presence of IL-12. Since DNT cells produce IFN-gamma, a potent inducer of IL-12, the INF-gamma induced-IL-12 may enhance lymphoaccumulation in MRL- lpr/lpr mice.